EP0805676A1 - Arzneimittel in tabletteform mit verzögerter wirkstoffabgabe auf basis von hochmolekularen polysaccharidgranulate - Google Patents

Arzneimittel in tabletteform mit verzögerter wirkstoffabgabe auf basis von hochmolekularen polysaccharidgranulate

Info

Publication number
EP0805676A1
EP0805676A1 EP96901859A EP96901859A EP0805676A1 EP 0805676 A1 EP0805676 A1 EP 0805676A1 EP 96901859 A EP96901859 A EP 96901859A EP 96901859 A EP96901859 A EP 96901859A EP 0805676 A1 EP0805676 A1 EP 0805676A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
matrix
composition according
polysaccharide
xanthan gum
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96901859A
Other languages
English (en)
French (fr)
Other versions
EP0805676B1 (de
Inventor
Jean-Pierre Collaueri
Guillaume Conrath
Paul-Jo[L Derian
Gabriel Gousset
Frédéric MAUGER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhodia Chimie SAS
Original Assignee
Rhone Poulenc Chimie SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Chimie SA filed Critical Rhone Poulenc Chimie SA
Publication of EP0805676A1 publication Critical patent/EP0805676A1/de
Application granted granted Critical
Publication of EP0805676B1 publication Critical patent/EP0805676B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

  • the present invention relates to pharmaceutical compositions in the form of prolonged-release tablets (also called delayed-release tablets) and to the process for their preparation.
  • the present invention relates to compositions of the above type, the tablets of which are based on granules of high molecular weight polysaccharides, more particularly based on granules of xanthan gum.
  • compositions of the above type contain a pharmacologically active principle and are used when it is desired to administer a medicament to a patient for an extended period of time without requiring the patient to take repeated doses at reduced intervals.
  • Direct compression is a particularly advantageous galenical process because it involves a limited number of operations and constituents and consequently requires for its implementation less expensive installations than for a process for preparing tablets by wet granulation.
  • not all pharmaceutical compositions can be obtained by this route.
  • Natural or synthetic hydrophilic gums which are high molecular weight polysaccharides are known as pharmaceutical excipients but not all gums can be used in long-acting compositions in dry compression processes for preparing tablets. These polysaccharides are either of microbial origin and are then obtained by fermentation of a carbohydrate which can be assimilated by an appropriate microorganism (example xanthan gum obtained from Xanthomonas campestris), or of natural origin such as, for example, guar gums and carob.
  • Xanthan gums are also known excipients for their possible use in the pharmaceutical field, in particular for the constitution of matrices intended for the preparation of controlled release forms.
  • hydrophilic gums in general and xanthan gum in particular are not used in the pre-granulated state.
  • WO-A 87/05212 teaches the preparation of long-acting tablets comprising a matrix formed of polysaccharides of natural origin, including xanthan gum.
  • EP-A 234 670 also teaches the preparation of long-acting tablets in which the matrix constitutes 7.5 to 28% by weight of the tablet, said matrix preferably comprising at least 75% by weight of xanthan gum.
  • non-pre-granulated xanthan gum especially at high content, that is to say generally at a content of about 30% by weight relative to the total weight of the tablet, to prepare a tablet by direct compression, leads to a tablet having many defects such as cleavages, heterogeneity, poor mechanical properties, etc.
  • An object of the present invention is to prepare a long-acting tablet based on high molecular weight polysaccharide, in particular based on xanthan gum, which can be prepared without difficulty by direct compression and having good release properties of the active principle and good mechanical properties.
  • a pharmaceutical composition in the form of delayed-effect tablets prepared by direct compression and consisting of at least one active principle and of a matrix giving its composition its effect. retardation, characterized in that said matrix consists at least in part of high molecular weight polysaccharide pregranules.
  • the high molecular weight polysaccharides which can be used in the context of the present invention include hydrophilic gums which may be of synthetic or natural origin.
  • the high molecular weight polysaccharides of synthetic origin are obtained by fermentation of a carbohydrate in the presence of microorganisms.
  • galactomanans As natural or modified natural polysaccharides, it is recommended to use galactomanans, glucomanans, succinoglycans. Scleroglucans, alginates, carrageenans, locust bean, guar, cassia and tara gums, starch, derivatives starch, pectins, chitosan, and their various possible mixtures.
  • Xanthan gum is the preferred polysaccharide.
  • modified polysaccharides is meant according to the invention more particularly their chemical derivatives such as for example hydroxypropylated derivatives or carboxymethylated derivatives of gums.
  • xanthan gum is recommended, the preparation of which is described in numerous publications such as US-A 3020 206, US-A 3 391 060 and US-A 4 154654.
  • Knutson they can be obtained by microbial fermentation of a medium comprising a carbon source, by means of a microorganism belonging to the genus Arthrobacter, such as Arthobacter stabilizer, in particular the strain Arthobacter stabilizer NRRL-B-1973, to the genus Agrobacterium, such Agrobacte ⁇ m tumefaciens, Agrobacterium radiobacter or Agrobacterium rhizogenes, in the genus Rhizobium, in particular Rhizobium m ⁇ liloti and Rhizobium trifoli, in the genus Alcaligenes, such Alcaligen ⁇ s faecalis, in particular the myxogenes variety or in the genus Pseudomonas, in particular the Pseudomo ⁇ strains.
  • Arthrobacter such as Arthobacter stabilizer, in particular the strain Arthobacter stabilizer NRRL-B-1973
  • Agrobacterium such Agrobacte ⁇ m tume
  • NCIB 11264 and NCIB 11592 are examples of succinoglycans.
  • the pregranules entering the pharmaceutical composition according to the invention are advantageously prepared starting from a polysaccharide powder, preferably Xanthan gum having a particle size such that 90% of the particles have a size less than 100 ⁇ m, preferably less at 75 ⁇ m.
  • the mean diameter is advantageously between 30 and 60 ⁇ m. By mean diameter is meant a diameter such that 50% by weight of the particles have a diameter less than or equal to this diameter.
  • any granulation process can be used, such as atomization, fluidized bed, extrusion, granulation by turntables, etc. or a combination of these processes.
  • GB-A 2086 204 describes a process of the same type.
  • the preferred granulation method is, according to the invention, the method according to which polysaccharide powder, preferably xanthan gum, is sprayed in a fluidized bed using a gas stream and is sprayed onto the powder, water optionally containing a surfactant and the granules are obtained by drying.
  • polysaccharide powder preferably xanthan gum
  • water optionally containing a surfactant and the granules are obtained by drying.
  • all the excipients in the matrix are co-granulated before being compressed.
  • pregranules whose average particle size is between 50 ⁇ m and 1000 ⁇ m, preferably between 100 and 350 ⁇ m and an apparent density between 0.3 and 0, 8 preferably between 0.35 and 0.7.
  • the polysaccharide may be the only constituent of the matrix.
  • the matrix may also contain one or more pharmaceutically acceptable excipients, more particularly diluents, cohesion agents, lubricating agents and coloring agents such as in particular saccharides, such as lactose and sucrose, fatty acids such as for example, stearic acid, polyethylene glycol, dicalcium phosphate, silica, silicoaluminates, cellulose derivatives, gelatin, polyvinylpyrrolidone and salts of fatty acids such as magnesium stearate.
  • the polysaccharide, and more particularly xanthan gum generally forms between
  • the matrix constitutes from 5 to 10
  • the amount of polysaccharide in the matrix is at least 20% by total weight of said matrix.
  • the amount of polysaccharide entering into the composition of the matrix is at most 50% by weight and preferably at most 40% by weight.
  • Lactose and / or dicalcium phosphate are the preferred co-excipients. These excipients can be co-granulated, if necessary, with the polysaccharide (s).
  • the proportion of the various ingredients can be varied very widely.
  • a delayed-effect release is desired in order to reduce the number of daily doses, but it is not going beyond the ambit of the invention to prepare a rapid-release pharmaceutical composition once it is used in the latter, polysaccharide pregranules.
  • the matrix when it is desired to obtain a pharmaceutical composition for rapid release of the active material, in addition to the polysaccharide, the matrix will more particularly comprise a higher proportion of lactose.
  • the matrix when it is desired to obtain a slow-release pharmaceutical composition, that is to say at least 12 hours, the matrix will comprise, in addition to the polysaccharide, a larger proportion of dicalcium phosphate.
  • the release kinetics also depend on the nature of the active ingredient and in particular on its greater or lesser solubility in water.
  • the content of active ingredient used in the pharmaceutical compositions of the invention can vary within wide limits. It is more particularly between 0.001 and 95% by weight of the total composition, the complement being provided by the matrix. It is preferably between 0.01 and 12% by weight. According to a preferred embodiment, it is advantageously between OJ and 10% by weight.
  • the present invention can be used for the direct compression of active ingredients belonging to all classes of drugs intended for oral administration.
  • active principles used in compositions according to the present invention there may be mentioned, without limitation, anti-rheumatic and non-steroidal anti-inflammatory drugs (ketoprofen, ibuprofen, flurbiprofen, indomethacin, phenylbutazone, allopurinol, nabumetone 10), analgesics opiates or not (paracetamol, phenacetin, aspirin ...), cough suppressants (codeine, codethyline, alimemazine %), psychotropics (trimipramine, amineptine, chlorpromazine and derivatives of phenothiazines, diazepam, lorazepam, nitrazepam, meprobamone, zopiclone and derivatives of the cyclopyrrolone family Among the active principles used in compositions according to the present invention, there may be
  • all the ingredients of the pharmaceutical composition can be dry compressed by direct compression, that is to say without the use of an organic solvent such as ethanol or its mix with water.
  • the compression operation following the mixing of the excipients and the active principle is generally carried out under a force which can range from 6 to
  • High compression speeds can be achieved by the method according to the invention, without altering the quality of the tablets. It is in particular possible to reach speeds greater than 150,000 tablets / hour, without causing cleavage.
  • the tablets obtained according to the invention can optionally be dandruff according to the usual methods.
  • the filming operation is facilitated by the fact that no cleavage occurs during the operation.
  • the tablets obtained according to the invention have the advantage of being able to modulate the release of the active principle but also of good mechanical properties, in particular the friability is less than 1%.
  • a pregranulated polysaccharide preferably xanthan gum
  • it has many advantages in terms of implementation.
  • it has very good flow properties, which favors the transfer, weighing, mixing and filling stages of the compression chambers.
  • the perfectly controlled particle size and the absence of fine particles make it possible to limit the phenomena of mixing and the risks associated with fine powders.
  • it has remarkable compressibility properties which facilitates the preparation of tablets.
  • the powder mixture consisting of the active ingredient (2 g), in this case Aprikalim and the various constituents of the matrix, namely the pregant granulated xanthan and optionally mixed in a SONECO® type mixer 700 g the other excipients, namely calcium phosphate and lactose.
  • the powder mixture also contains the lubricating agent (7 g), namely magnesium stearate, therefore dosed at 1% by weight in said powder mixture.
  • the compression is carried out under a force of 8.5 kN (measured at the level of the compression roller) using a rotary machine of the MANESTY® type which makes it possible, from 700 g of powder mixture, 2000 tablets 350 mg each, so containing 1 mg of Aprikalim.
  • the powder mixture also undergoes pre-compression under a force of 1.5 kN.
  • Pre-granulated xanthan gum (Rhodigel Easy® sold by Rhône-Poulenc) is used, 95% by weight of the granules having a particle size between 150 and 250 ⁇ m and an apparent density of 0.5 g / cm 3, prepared according to the technique of fluidized bed described in particular in French patent FR-A 2600267.
  • the matrices of Examples 1 to 18 have different contents of excipients which are collated in Table 1 below.
  • Examples 10 and 17 The procedure of Examples 10 and 17 is exactly repeated except that the xanthan gum granules are replaced by standard non-pregranulated xanthan gum (Rhodigel® marketed by Rhône Poulenc) having a particle size centered on 100 ⁇ m, containing 40% of fines having a particle size between 35 and 50 ⁇ m. Powder mixtures have poor compressibility.
  • the tests for manufacturing tablets have not been conclusive, the tablets obtained having no minimum cohesion and having too great a cleavage phenomenon.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP96901859A 1995-01-27 1996-01-26 Arzneimittel in tablettenform mit verzögerter wirkstoffabgabe auf basis von hochmolekularen polysaccharidgranulaten Expired - Lifetime EP0805676B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9500946A FR2729857B1 (fr) 1995-01-27 1995-01-27 Compositions pharmaceutiques sous forme de comprimes a liberation prolongee a base de granules en polysaccharides de haut poids moleculaire
FR9500946 1995-01-27
PCT/FR1996/000133 WO1996022767A1 (fr) 1995-01-27 1996-01-26 Compositions pharmaceutiques sous forme de comprimes a liberation prolongee a base de granules en polysaccharides de haut poids moleculaire

Publications (2)

Publication Number Publication Date
EP0805676A1 true EP0805676A1 (de) 1997-11-12
EP0805676B1 EP0805676B1 (de) 1999-12-15

Family

ID=9475564

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96901859A Expired - Lifetime EP0805676B1 (de) 1995-01-27 1996-01-26 Arzneimittel in tablettenform mit verzögerter wirkstoffabgabe auf basis von hochmolekularen polysaccharidgranulaten

Country Status (10)

Country Link
US (1) US6221393B1 (de)
EP (1) EP0805676B1 (de)
JP (1) JPH10512873A (de)
AT (1) ATE187640T1 (de)
AU (1) AU4627096A (de)
CA (1) CA2210321C (de)
DE (1) DE69605649T2 (de)
ES (1) ES2143180T3 (de)
FR (1) FR2729857B1 (de)
WO (1) WO1996022767A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
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WO2015170038A1 (fr) 2014-05-05 2015-11-12 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Co-granules de gomme de xanthane et de gomme d'acacia

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US5478577A (en) * 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
FR2785191B1 (fr) * 1998-11-02 2002-05-31 Rhodia Chimie Sa Utilisation de gommes xanthanes pour la preparation de compositions pharmaceutiques
BR0205722A (pt) * 2001-07-06 2005-04-05 Penwest Pharmaceuticals Compan Formulação de liberação prolongada e método para o tratamento de um paciente que sofre de dor
CN1551770A (zh) * 2001-07-06 2004-12-01 ������ҩ�����޹�˾ 羟吗啡酮控释制剂
CA2459976A1 (en) * 2001-09-26 2003-04-03 Penwest Pharmaceuticals Company Opioid formulations having reduced potential for abuse
CA2498798A1 (en) * 2002-09-20 2004-04-01 Alpharma, Inc. Sustained-release opioid formulations and methods of use
RS20050714A (sr) * 2003-03-31 2008-04-04 Pliva-Lachema A.S., Farmaceutski preparati koji kao aktivnu suptancu sadrže kompleks platine i postupci za njihovo dobijanje
US20050042289A1 (en) * 2003-04-29 2005-02-24 Yamanouchi Pharma Technologies, Inc. Tablets and methods for modified release of hydrophylic and other active agents
WO2005005484A1 (ja) 2003-07-11 2005-01-20 Asahi Kasei Chemicals Corporation 機能性澱粉粉末
US7999003B2 (en) * 2003-08-26 2011-08-16 Mannatech, Incorporated Antioxidant compositions and methods thereto
ES2403069T3 (es) * 2005-02-22 2013-05-13 Sun Pharma Advanced Research Company Ltd Composición oral de liberación controlada que contiene levetiracetam
US20070036859A1 (en) * 2005-08-11 2007-02-15 Perry Ronald L Sustained release antihistamine and decongestant composition
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
WO2008011187A2 (en) * 2006-07-20 2008-01-24 Rhodia Inc. Method for making derivatized guar gum and derivatized guar gum made thereby
CN101578096A (zh) * 2006-10-10 2009-11-11 潘威斯脱药物公司 稳健的缓释制剂
US20080085304A1 (en) * 2006-10-10 2008-04-10 Penwest Pharmaceuticals Co. Robust sustained release formulations
EP2568968B1 (de) 2010-05-10 2017-07-12 Euro-Celtique S.A. Herstellung von Wirkstoff-freiem Granulat und dieses enthaltende Tabletten

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IT1191674B (it) * 1986-03-07 1988-03-23 Eurand Spa Formulazioni per la preparazione di farmaci a rilascio prolungato adatte alla somministrazione per via orale
FR2600267A1 (fr) * 1986-06-19 1987-12-24 Rhone Poulenc Chimie Granules de biopolymere a dispersabilite et dissolution rapides
US4994276A (en) * 1988-09-19 1991-02-19 Edward Mendell Co., Inc. Directly compressible sustained release excipient
US5169639A (en) * 1988-09-19 1992-12-08 Edward Mendell Co., Inc. Controlled release verapamil tablets
US5077051A (en) * 1990-04-10 1991-12-31 Warner-Lambert Company Sustained release of active agents from bioadhesive microcapsules
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2015170038A1 (fr) 2014-05-05 2015-11-12 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Co-granules de gomme de xanthane et de gomme d'acacia

Also Published As

Publication number Publication date
ES2143180T3 (es) 2000-05-01
JPH10512873A (ja) 1998-12-08
WO1996022767A1 (fr) 1996-08-01
DE69605649T2 (de) 2000-06-21
MX9705611A (es) 1997-10-31
CA2210321A1 (fr) 1996-08-01
FR2729857B1 (fr) 1997-04-04
FR2729857A1 (fr) 1996-08-02
AU4627096A (en) 1996-08-14
CA2210321C (fr) 2003-03-18
EP0805676B1 (de) 1999-12-15
ATE187640T1 (de) 2000-01-15
DE69605649D1 (de) 2000-01-20
US6221393B1 (en) 2001-04-24

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